Assessment of noninvasive brain stimulation interventions in Parkinson’s disease: a systematic review and network meta-analysis

A network meta-analysis of randomized controlled trials was conducted to compare and rank the effectiveness of various noninvasive brain stimulation (NIBS) for Parkinson's disease (PD). We searched PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) databases from the date of database inception to April 30th, 2024. Two researchers independently screened studies of NIBS treatment in patients with PD based on inclusion and exclusion criteria. Two researchers independently performed data extraction of the included studies using an Excel spreadsheet and assessed the quality of the literature according to the Cochrane Risk of Bias Assessment Tool (RoB2). Network meta-analysis was performed in StataMP 17.0. A total of 28 studies involving 1628 PD patients were included. The results showed that HF-rTMS over the SMA (SMD = − 2.01; 95% CI [− 2.87, − 1.15]), HF-rTMS over the M1 and DLPFC (SMD = − 1.80; 95% CI [− 2.90, − 0.70]), HF-rTMS over the M1 (SMD = − 1.10; 95% CI [− 1.55, − 0.65]), a-tDCS over the DLPFC (SMD = − 1.08; 95% CI [− 1.90, − 0.27]), HF-rTMS over the M1 and PFC (SMD = − 0.92; 95% CI [− 1.71, − 0.14]), LF-rTMS over the M1 (SMD = − 0.72; 95% CI [− 1.17, − 0.28]), and HF-rTMS over the DLPFC (SMD = − 0.70; 95% CI [− 1.21, − 0.19]) were significantly improved motor function compared with sham stimulation. The SUCRA three highest ranked were HF-rTMS over the SMA (95.1%), HF-rTMS over the M1 and DLPFC (89.6%), and HF-rTMS over the M1 (73.0%). In terms of enhanced cognitive function, HF-rTMS over the DLPFC (SMD = 0.80; 95% CI [0.03,1.56]) was significantly better than sham stimulation. The SUCRA three most highly ranked were a-tDCS over the M1 (69.8%), c-tDCS over the DLPFC (66.9%), and iTBS over the DLPFC (65.3%). HF-rTMS over the M1 (SMD = − 1.43; 95% CI [− 2.26, − 0.61]) and HF-rTMS over the DLPFC (SMD = − 0.79; 95% CI [− 1.45, − 0.12)]) significantly improved depression. The SUCRA three highest ranked were HF-rTMS over the M1 (94.1%), LF-rTMS over the M1 (71.8%), and HF-rTMS over the DLPFC (69.0%). HF-rTMS over the SMA may be the best option for improving motor symptoms in PD patients. a-tDCS and HF-rTMS over the M1 may be the NIBS with the most significant effects on cognition and depression, separately. Trial registration: International Prospective Register of Systematic Review, PROSPERO (CRD42023456088)


Inclusion and exclusion criteria
The inclusion criteria included: (1) Patient: adults (≥ 18 years) with PD who meet the diagnostic criteria for PD, regardless of gender, race, or disease severity; (2) Intervention: NIBS stimulation, with an unlimited number of NIBS sessions, stimulation parameters, and target locations; The exclusion criteria included: (1) duplicate publications or duplicate literature data; (2) study data not available; (3) not RCT;(4) protocol but not report of study result.

Study selection and data extraction
Two researchers independently screened titles and abstracts after removing duplicates and subsequently reviewed the full text based on predetermined criteria to identify eligible studies and perform data extraction.Any disagreements were resolved through discussion with the third researcher.The following information was independently extracted for the included studies using an Excel sheet: first author, time of publication, number of

Risk of bias assessment
According to the Cochrane risk of bias tool (RoB2), two researchers individually assessed each of the five sections: randomization process, deviations from intended interventions, missing outcome data, measurement of outcome, and selection of reported result 26 .We determined the risk of bias to be low, some concerns, or high by using the RoB2 to answer important questions for each of these sections.If each section is low risk, the overall risk of bias is "low risk"; if more than one section is "some concerns" and there is no "high risk", the overall risk of bias is "some concerns"; as long as one section is "high risk", the overall risk of bias is "high risk".Inconsistent evaluations were discussed and finalized with the third researcher.

Data synthesis and analysis
The outcome measures in this study were continuous variables, and the mean and standard deviation (SD) of the change in scores in each scale before and after treatment were calculated according to the formulas in the Cochrane Handbook for Systematic Reviews of Interventions to eliminate baseline differences 26 .
Network meta-analysis was performed in StataMP 17.0 using the "network meta" command.A network relationship plot was performed in which the circles indicate the sample size of included studies, and the straight lines indicate the number of studies between the two interventions.When a closed loop exists, direct and indirect comparison consistency was assessed using the node-splitting method, with P > 0.05 indicating good consistency, which can be analyzed using the consistency model, and vice versa using the inconsistency model.In addition, we evaluated the efficacy of different sham NIBS stimulations using pairwise meta-analysis with the Comprehensive Meta-Analysis software 3.7 to demonstrate the assumption of transitivity of network meta-analysis 27,28 .Forest plots of NIBS compared to sham stimulation were drawn.League tables for pairwise meta-analysis were made.The surface under the cumulative ranking curve (SUCRA) was calculated to perform the superiority ranking of the interventions.The closer the SUCRA value was to 100%, the higher the probability that the intervention would be optimal.Funnel plots were drawn for publication bias analysis.
We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) rating tool to assess the quality of the analyzed evidence 29 .We assessed quality by categorizing the outcome indicators into four levels high quality, moderate quality, low quality, and very low quality based on five dimensions: study limitations, imprecision, inconsistency, indirectness, and publication bias.

Assessment of motor function improvement
As shown in Fig. 3A, the network meta-analysis reporting motor function in patients with PD contains 12 interventions that form 14 pairs of direct comparisons.The node-splitting method reports that this closedloop local inconsistency is not significant (Supplementary Table S3).The sham NIBS treatment effect was not statistically different between sham iTBS, sham rTMS, and sham tDCS treatments (P = 0.378) (Supplementary Figure 1).The pairwise meta-analysis of NIBS compared with sham stimulation showed that HF-rTMS over the SMA (SMD = − 2. www.nature.com/scientificreports/(95.1%) ranked the highest probability of being the best therapy, followed by HF-rTMS over the M1 and DLPFC (89.6%) and HF-rTMS over the M1 (73.0%) (Fig. 5A, Table 3).

Assessment of cognitive function improvement
As shown in Fig. 3B, the network meta-analysis reporting cognitive functioning in patients with PD contains 10 interventions that form 11 pairs of direct comparisons.The node-splitting method shows no significant local inconsistency in this network plot (Supplementary Table S4).The difference in the efficacy of sham NIBS treatment was not significant between sham iTBS, sham rTMS, and sham tDCS treatments (P = 0.055) (Supplementary Figure 2).However, the efficacy was significant in the sham tDCS group (SMD = 1.052; 95% CI [0.599, 1.504]).

Publication bias
Funnel plots using motor function, cognitive function, and depression status as outcome indicators were all generally symmetrical, suggesting no significant publication bias (Fig. 6A-C).

GRADE ratings
The results of the GRADE evaluation are shown in Table 8.In summary, the overall quality of the overall evidence was low to moderate.It was mainly due to some risk of bias in the included studies, 95% confidence intervals

Identification of studies via databases and registers
Records identified in the database search (n=3051) Removed due to full text (n=76)

Discussion
This study is based on 28 RCTs using network meta-analysis to assess the efficacy of different NIBS in the treatment of PD and to help in choosing the best option for clinical treatment.We found that most NIBS protocols improved motor function in patients with PD.Specifically, HF-rTMS over the SMA was found to be most effectively associated with improved motor function.In terms of cognitive function, SUCRA results showed that a-tDCS over the M1 was considered most effectively associated with its improvement.Notably, the results of pairwise meta-analysis showed that only HF-rTMS over the DLPFC was significantly more efficacious than the sham stimulation group in the different NIBS.HF-rTMS over the M1 was found to be most effectively associated with improved depression.A primary finding of the study results was that HF-rTMS was effective in improving motor dysfunction in patients with PD, which is consistent with the conclusions of a previous network meta-analysis 58 .We further comparatively investigated the target areas of action of rTMS and found that SMA may be more effective in the treatment of motor disorders.SMA is a key brain region that connects the motor and cognitive nervous systems and plays an important role in motor preparation and control 59 .SMA dysfunction is considered to be an important cause of continuous motor abnormalities and gait disturbances in PD patients.Resting-state functional magnetic resonance imaging study showed significant differences in functional connectivity in sensorimotor, insula, and cerebellum networks between PD patients and healthy individuals 60 .
The second primary finding of the study results is that a-tDCS over the M1 and HF-rTMS over the M1 may be better for cognition and depression separately.However, there was no statistically significant difference in efficacy between a-tDCS over the M1 compared to the sham stimulation group.Therefore, these findings should be interpreted cautiously to ensure that future large-scale randomized controlled trials provide additional evidence.Patients with PD suffer from dopamine neuronal damage in the dense midbrain substantia nigra and dopamine deficiency in the striatum 61 .The substantia nigra contains the largest network of dopaminergic cells in the brain and is involved in the regulation of motor, emotional and cognitive behavior 62 .It was found that rTMS over the M1 region induced endogenous dopamine release in the ventral striatum, which may be its intrinsic mechanism for the treatment of PD 63 .In addition, HF-rTMS over the DLPFC demonstrated favorable improvement in cognition and depression.DLPFC is a core brain region of the central executive network, which is closely related to executive function, attention, and visuospatial ability.It was shown that mood changes in PD patients may be closely related to decreased activity in the left DLPFC.There is still a need for in-depth research on the mechanism of action of NIBS to improve PD, to reveal the scientific basis of its efficacy from neurophysiological and biochemical perspectives, and to conduct large-scale comparative efficacy studies on different targets.
Potential limitations of this study are: (1) inconsistencies in patient age, duration of illness, and severity among the studies included in the analysis may have increased study heterogeneity and affected the results of the analysis; (2) most of the included studies did not explicitly report or implement allocation concealment processes, and more than half of the studies did not implement evaluator blinding; (3) due to language limitations, the literature included in the present study covered only the English and Chinese literature, there is a possibility of incomplete search.

Conclusions
In summary, HF-rTMS over the SMA may be the best option for improving motor symptoms in PD patients.a-tDCS and HF-rTMS over the M1 may be the NIBS with the most significant effects on cognition and depression, separately.A large number of future RCTs are needed to investigate the efficacy of NIBS in patients with Parkinson's disease and the optimal combination of appropriate parameters, including stimulation frequency and stimulation target.

( 3 )
Comparator: sham NIBS; (4) Outcomes: indicators of motor function were the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III); indicators of cognitive function assessment in non-motor function were the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA); indicators of depression assessment in non-motor function were the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS); (5) randomized controlled trials (RCTs).

Figure 4 .
Figure 4. Forest plots for direct comparison with sham stimulation.(A) motor function (B) cognitive function (C) depression.

Table 2 .
League table of the changes of motor function.Bold results marked with indicate statistical significance.

Table 3 .
SUCRA of the changes of motor function.

Table 4 .
League table of the changes of cognitive function.Bold result marked with indicate statistical significance.

Table 5 .
SUCRA of the changes of cognitive function.

Table 6 .
League table of the changes of depression.Bold results marked with indicate statistical significance.

Table 7 .
SUCRA of the changes of depression.

Table 8 .
GRADE evaluation quality of evidence.We grade based on the following criteria estimates.(1)Studylimitations:Wedowngraded by one level when the contributions from low RoB2 comparisons were less than 30% and contributions from moderate RoB2 comparisons were 70% or greater.(2)Imprecision:Wedeterminedwhether the confidence intervals crossed the clinical decision thresholds for recommended and non-recommended treatments.If it crossed it was downgraded for imprecision.(3)Inconsistency:Webasedour ratings on heterogeneity tests and inconsistency tests.Downgrade if there is significant heterogeneity (I 2 > 50%) or inconsistency (P < 0.05).(4)Indirectness:Weanalyzed the efficacy of different sham NIBS by pairwise meta-analysis methods to ensure network transitivity.The results of our analysis proved the transitivity (P > 0.05).(5)Publication bias: We assessed this based on the symmetry of the comparisoncorrection funnel plot and the funding sources and stakes of the included study.